Efficacy of pimecrolimus in infants

The efficacy of pimecrolimus for the treatment of AD in infants has been extensively evaluated in multiple vehicle-controlled pivotal trials (Table 1 ). These trials have consistently demonstrated that topical pimecrolimus treatment results in effective long-term control of AD in infants (46-50). Twice-daily application of pimecrolimus in infants effectively reduced the risk for flares compared with vehicle, with 67.6% versus 30.4% of patients completing 6 months without flares (P <.001), resulting in an absolute risk reduction of 37.2%, which was independent of baseline severity (47). Additionally, the mean Eczema Area and Severity Index (EASI) was already reduced by approximately 70 – 80% after 4 weeks of pimecrolimus treatment, while there was no symptom relief at this timepoint for infants who were treated with vehicle control (46, 50). Furthermore, this response was irrespective of disease severity and significant even for infants with very severe disease (Investigator’s Global Assessment [IGA] ≥4) (46). The earliest significant reduction in EASI was reported from day 4 onwards, with a reduction of 38.5% and 17.6% after 4 days of pimecrolimus and vehicle treatment, respectively (P <.001) (46). Importantly, the early and sustained treatment success (IGA 0 or 1) observed in the head and neck area was similar to that of the whole body. A rapid response in sensitive skin areas is especially important in infants who mostly have a sensitive skin structure to decrease the disease burden as early as possible (46). Furthermore, disease control with pimecrolimus was proven to be long-term, with approximately 70% of patients having minimal or no disease, as assessed by the IGA score and EASI, after 2 years of intermittent pimecrolimus treatment (48). Similar to the reductions seen in EASI and IGA scores, pimecrolimus effectively relieved pruritus, which was associated with significant improvements in the QoL and sleep behavior of the infant. Already within the first week of use, 70% of infant patients reported absence of mild pruritus compared to about half of the patients treated with vehicle (46-48, 50-52). Also, parents experienced significant improvements in psychosomatic well-being, social life, confidence in medical treatment, and emotional coping after 4 weeks of treatment of their infants (51). These improvements in QoL of parents were found to be sustained up to 1 year of treatment and probably thereafter, as they coincided with long-term disease control of their infants (52). Although not evaluated in this study, such impact on QoL presumably also decreases the substantial economic burden of the disease. In the vehicle-controlled trials, use of pimecrolimus was found to decrease over the course of long-term treatment upon clearance of symptoms, but importantly discontinuation was not associated with rebound flares, as has been described for TCS (46, 48, 53). Pimecrolimus treatment also had a steroid-sparing effect in the infant, which was reflected by a decrease in overall use and an increased time to first use of TCS as well as a reduced number of days on TCS therapy (47, 49).
Head-to-head comparisons between pimecrolimus and tacrolimus in the pediatric population were assessed in two RCTs, which evaluated both treatments in children of 2 to 17 years of age (54, 55). These two trials were also included in a meta-analysis, demonstrating that pimecrolimus and tacrolimus have comparable efficacy in children with AD (56). However, to the best of our knowledge, there is only one 24-month open-label phase II clinical trial evaluating safety and efficacy of tacrolimus in 50 infants below the age of 2 years, indicating additional studies are needed to evaluate tacrolimus for the infant indication (57).
To support the use of pimecrolimus as an alternative treatment to TCS in infants, the PETITE study was designed to compare the long-term safety and efficacy of TCS and pimecrolimus for the treatment of infants with AD in a real-world setting (58). In total, 2,418 infants aged between 3 and 12 months were randomized to receive either pimecrolimus (n=1,205) or mild-to-moderate potency TCS (n=1,213) (58). However, short-term use of TCS was allowed in case disease flares could not be controlled by pimecrolimus treatment. The PETITE study confirmed the previous results from the vehicle-controlled trials, showing that pimecrolimus relieved symptoms in more than 50% of patients already after 3 weeks of treatment. The onset of disease control was comparable between pimecrolimus and TCS, and treatment with both anti-inflammatory drugs resulted in almost complete clearance of symptoms in more than 85% of patients after 1.5 years of intermittent treatment. Accordingly, less than 5% of body surface area was affected in week 3, with no eczematous lesions after 1.5 year of treatment in both groups which was maintained until the end of the study (58). Importantly, pimecrolimus was steroid-sparing, as 36% of patients in the pimecrolimus group did not use any TCS during the 5 years follow-up period (58). Whether or not the reduced need for TCS improves treatment adherence by overcoming concerns related to corticophobia remains to be formally demonstrated. However, it is well-established that use of TCS is causing epidermal thinning and skin atrophy, while pimecrolimus can restore certain aspects of the epidermal barrier (22). As infants overall have a sensitive structure of the skin, this is an additional factor favoring long-term use of pimecrolimus over TCS for infants with AD.
So far, the Study of the Atopic March (SAM) is the only RCT that examined the impact of pimecrolimus versus vehicle treatment on the development of atopic comorbidities in infants with AD (30, 33). This initial study found no effect of early pimecrolimus treatment on the development of atopic comorbidities which may be at least partially attributed to the unexpectedly high discontinuation rate (48%) due the fact that the trial was conducted just after implementation of the black-box warning for pimecrolimus (30, 33). Nevertheless, rates of food allergies, asthma, and allergic rhinitis were all lower than previously reported, not excluding an effect of early treatment (30). Additionally, most infants were not presenting with severe disease and rescue therapy with TCS was permitted in both treatment groups, which may have compromised the results (30). Due to the aforementioned limitations, it remains currently unclear whether early intervention with pimecrolimus for treatment of AD in infants may prevent the development of atopic comorbidities.